Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). Recently, the sequence of another heretofore unknown enzyme in the human arachidonic acid/prostaglandin pathway has been reported by T. Hla and K. Nielson, Proc. Natl. Acad. Sci, USA, 89, 7384 (1992) and named "cyclooxygenase II (COX II)" or "prostaglandin G/H synthase II". The discovery of an inducible enzyme associated with inflammation provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects. Cyclooxygenase II is inducible by cytokines or endotoxins and such induction is inhibited by glucocortoids (J. Masferrer, et al, Proc. Natl. Acad. Sci, USA, 89, 3917 (1992)). The 6-methoxy-2-napthylacetic acid metabolite of nabumetone has been found by E. Meade et al to selectively inhibit the COX II enzyme (J. Biol. Chem., 268, 6610 (1993)). In addition, Futaki et al (Prostaglandins, 47, 55 (1994)) have reported that N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide inhibits the COX II enzyme.
The references below that describe antiinflammatory activity, show continuing efforts to find a safe and effective antiinflammatory agent. The novel imidazoles described herein are such safe and also effective antiinflammatory agents furthering such efforts. The invention compounds are found to show usefulness in vivo as antiinflammatory agents with minimal side effects. The substituted imidazolyl compounds described herein preferably selectively inhibit cyclooxygenase II over cyclooxygenase I.
U.S. Pat. No. 4,822,805, to Takasugi et al, describes pyridyl-imidazoles as antiinflammatory agents. Specifically, 2-[2-methoxy-4-(methylsulfonyl)phenyl]-4-methyl-5-(3pyridyl)imidazole is described.
U.S. Pat. No. 4,188,397, to Hill, describes 2,2-alkyldiylbis(thio)bis(imidazoles) with substituted phenyl radicals am the 4 and 5 positions of the imidazole rings as having antiinflammatory activity. Specifically, imidazoles having phenyl radicals substituted with methoxy, methylthio, trifluoromethylhalo and methylenedioxy are described.
T. Sharpe et al [J. Med. Chem., 28, 1188 (1985)] describe antiarthritic activity of 4,5-diaryl-2-(substituted thio)-1H-imidazoles.
U.S. Pat. No. 4,686,231, to Bender et al, describes 4,5-diaryl-1H-imidazoles as inhibiting the 5-lipoxygenase pathway for the treatment of arthritis. 1-Methyl-4,5-bis(methoxyphenyl)-2-methylthio-1H-imidazole ms specifically described.
Australian publication AU8665565 describes cyano-2,2-bis(imidazoles) as having antihypertensive agents.
H. Greenberg et al [J. Org. Chem., 31, 3951 (1966)] describe 4-(2-oxo-5-phenyl-4-imidazolin-4-yl)benzenesulfonamide in a study of the bromination reaction thereof.
T. van Es and O. Backeberg [J. Chem. Soc., 1363 (1963)] describe the synthesis of [4,4'-imidazol-4,5-diyl]bis(benzenesulfonamide) for use in a study of substitution reactions on phenyl radicals.
European publication EP 372,445, published Jun. 13, 1990, describes 4,5-diaryl-1H-imidazoles as having antihypercholesterolemic activity. N-[[5-(4-Methylsulfonylphenyl)-4-phenyl-1H-imidazo1-2-yl]thio]pentyl-N-oct yl-N-heptylurea is specifically described.
U.S. Pat. No. 4,503,065, to Wilkerson, describes 4,5-diaryl-2-halo-1H-imidazoles as being antiinflammatory. Specifically, 1-(1-ethoxyethyl)-2-fluoro-4,5-bis(4-methylsulfonylphenyl)-1H-imidazole is described.
J. Lombardino (J. Med. Chem., 17, 1182 (1974)) describes trisubstituted imidazoles as being antiinflammatory, and specifically 4,5-bis(4-methoxyphenyl)-2-trifluoromethyl-1H-imidazole. Similarly, U.S. Pat. No. 3,707,475, to Lombardino, describes antiinflammatory 4,5-diarylimidazoles. Specifically, 4-chlorophenyl-5-(4-methylthiophenyl)-2-trifluoromethyl-1H-imidazole is described.
U.S. Pat. No. 4,472,422, to Whitney, describes 4,5-diaryl-1H-imidazole-2-methanamines as having antiinflammatory activity. Specifically, 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-.alpha.,.alpha.-bis(trifluor omethyl)-1H-imidazole-2-methanamine is described.
U.S. Pat. No. 4,372,964, to Whitney, describes 4,5-diaryl-1H-imidazole-2-methanols as having antiinflammatory activity. Specifically, 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-.alpha.,.alpha.-bis(trifluor omethyl)-1H-imidazole-2-methanol is described. Additionally, Whitney describes 1-[4,5-diaryl-1H-imidazol-2-yl]-2,2,2-trifluoro-1-ethanones as having antiinflammatory activity. Specifically, 1-[5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-1H-imidazol-2-yl]-2,2,2-t rifluoro-1-ethanone is described.
U.S. Pat. No. 4,576,958, to Wexler, describes 4-phenyl-5-(4-methylsulfonylphenyl)-1H-imidazoles as having antiinflammatory activity. Specifically, 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-.alpha.,.alpha.-bis(trifluor omethyl-1H-imidazole-2-methanol and 4-(4-fluorophenyl)-5-4-methylsulfonylphenyl)-.alpha.,.alpha.-bis(trifluoro methyl-1H-imidazole-2-methanol, acetate is described.
U.S. Pat. No. 3,901,908, to Fitzi, et al, describes 2-alkyl-4,5-bis(substituted phenyl)-1H-imidazoles. Specifically, 2-tert-butyl-4-(4-methylsulfonylphenyl)-5-phenyl-1H-imidazole is described.